Discover Portal

NIHR Signal Cognitive behavioural therapy may not work for people with schizophrenia who haven’t completely responded to drug treatment

Cognitive behavioural therapy (CBT) does not improve residual symptoms for people taking clozapine for schizophrenia. Clozapine is the gold-standard antipsychotic that is used when others have not worked.

This NIHR-funded UK trial included 487 adults who had been taking clozapine for on average five years but were still symptomatic. Participants received either weekly CBT for nine months alongside usual treatment for schizophrenia or usual treatment alone. Usual treatment included clozapine or other medication and care from secondary, community or inpatient mental health services.

There were no differences in favour of CBT at the main time-point of 12 months after the end of treatment though there was a minimal benefit at the end of the nine months course. NICE recommends CBT at any stage of schizophrenia. Though the results did not support CBT for people with treatment resistant schizophrenia, it may be that timing and individual preferences need to be taken into account to decide when this form of therapy may be most beneficial.

The study highlights the need for alternative treatments to be developed.

Share your views on the research.

Why was this study needed?

Schizophrenia is a mental illness that affects around 220,000 people in the UK. The main symptoms are psychosis, hearing or seeing things that aren’t there (hallucinations) or fixed, false beliefs that are not based in reality (delusions). Other symptoms can include self-neglect and social withdrawal. It currently accounts for 30% of all spending on adult mental health services in the NHS.

Approximately one third of people with a diagnosis of schizophrenia respond poorly to recommended medical treatments. Clozapine is commonly prescribed for those who cannot tolerate or do not respond to other treatments, but 30-40% of them still have an inadequate response. It can also result in adverse effects, especially when used in combination with additional antipsychotic medication. For those who have treatment-resistant schizophrenia, personal, social and financial outcomes can be poor.

CBT is recommended alongside antipsychotic medication for schizophrenia, though it was unclear whether it can help people with symptoms, even though they are on drugs. This study aimed to determine whether CBT is clinically effective for people with clozapine resistant schizophrenia.

What did this study do?

The FOCUS randomised controlled trial was conducted at five sites across the UK and included 487 adults with schizophrenia and continued psychotic symptoms. They were randomly assigned to receive usual treatment plus weekly CBT for nine months or to remain on usual treatment, provided by secondary mental health services.

The average age of participants was 42 years and they had been diagnosed with schizophrenia or schizoaffective disorder for 11 to 25 years. Most were white, unemployed men living independently. On average they had been taking clozapine for five years, though 10% had discontinued it. Half were also taking antidepressants.

The CBT followed a validated method developed by the lead researcher for psychosis. It was delivered by qualified psychological therapists.

Assessors were unaware of treatment allocation, which reduces the risk of bias.

What did it find?

CBT slightly improved symptoms at the end of the nine months treatment period according to the Positive and Negative Syndrome Scale (PANSS, range 30 to 210 with higher scores worse). The score decreased from 82.8 to 75.2 in the CBT group and from 83.3 to 77.8 in the control group (mean difference [MD] -2.40, 95% confidence interval [CI] -4.79 to -0.02).

Twelve months later, the important time-point to the researchers, there was no difference in PANSS score, at 73.0 in the CBT group and 74.1 in the control group (MD ‑0.98, 95% CI -3.32 to 1.55).

There were no differences between the two groups on other self-rated quality of life scales including the health status and health-related utility (EQ-5D-5L) and the Questionnaire about the Process of Recovery (QPR).

CBT seemed to be an acceptable treatment. 88% attended six or more sessions, and the median number was 21 sessions.

The study found no evidence that CBT caused any adverse events.

What does current guidance say on this issue?

NICE 2014 guidelines recommend offering CBT to all people with schizophrenia. This includes people who have persistent psychotic symptoms, those who are withdrawn and also people in remission. The aim is to promote recovery. It is recommended that CBT consist of at least 16 planned sessions.

CBT, family therapy and art therapy are the main three psychological interventions available for any stage of schizophrenia.

What are the implications?

In this group of people with longstanding schizophrenia and continued symptoms despite the use of clozapine, CBT was an ineffective addition to usual care. This trial does not support the widespread use of CBT in this group of people

People who had received CBT within the previous year were excluded from the trial, and it is unclear how many of the participants had ever been offered or engaged with CBT or other psychological therapy. Therefore it is difficult to know whether there is a subgroup who would benefit more. There may also be a timing issue of starting therapy when a person is ready to do so, rather than in the confines of a trial.

Though the results are disappointing, it highlights the need for alternative options to be developed. It should also not preclude CBT from being offered on an individual basis.

This study was funded by the National Institute for Health Research Health Technology Assessment programme (project number 10/101/02).
Conflicting interests are declared by some of the co-authors. The CBT manual used in this study was developed by the lead researcher.

Why was this study needed?

Schizophrenia is a mental illness that affects around 220,000 people in the UK. The main symptoms are psychosis, hearing or seeing things that aren’t there (hallucinations) or fixed, false beliefs that are not based in reality (delusions). Other symptoms can include self-neglect and social withdrawal. It currently accounts for 30% of all spending on adult mental health services in the NHS.

Approximately one third of people with a diagnosis of schizophrenia respond poorly to recommended medical treatments. Clozapine is commonly prescribed for those who cannot tolerate or do not respond to other treatments, but 30-40% of them still have an inadequate response. It can also result in adverse effects, especially when used in combination with additional antipsychotic medication. For those who have treatment-resistant schizophrenia, personal, social and financial outcomes can be poor.

CBT is recommended alongside antipsychotic medication for schizophrenia, though it was unclear whether it can help people with symptoms, even though they are on drugs. This study aimed to determine whether CBT is clinically effective for people with clozapine resistant schizophrenia.

What did this study do?

The FOCUS randomised controlled trial was conducted at five sites across the UK and included 487 adults with schizophrenia and continued psychotic symptoms. They were randomly assigned to receive usual treatment plus weekly CBT for nine months or to remain on usual treatment, provided by secondary mental health services.

The average age of participants was 42 years and they had been diagnosed with schizophrenia or schizoaffective disorder for 11 to 25 years. Most were white, unemployed men living independently. On average they had been taking clozapine for five years, though 10% had discontinued it. Half were also taking antidepressants.

The CBT followed a validated method developed by the lead researcher for psychosis. It was delivered by qualified psychological therapists.

Assessors were unaware of treatment allocation, which reduces the risk of bias.

What did it find?

CBT slightly improved symptoms at the end of the nine months treatment period according to the Positive and Negative Syndrome Scale (PANSS, range 30 to 210 with higher scores worse). The score decreased from 82.8 to 75.2 in the CBT group and from 83.3 to 77.8 in the control group (mean difference [MD] -2.40, 95% confidence interval [CI] -4.79 to -0.02).

Twelve months later, the important time-point to the researchers, there was no difference in PANSS score, at 73.0 in the CBT group and 74.1 in the control group (MD ‑0.98, 95% CI -3.32 to 1.55).

There were no differences between the two groups on other self-rated quality of life scales including the health status and health-related utility (EQ-5D-5L) and the Questionnaire about the Process of Recovery (QPR).

CBT seemed to be an acceptable treatment. 88% attended six or more sessions, and the median number was 21 sessions.

The study found no evidence that CBT caused any adverse events.

What does current guidance say on this issue?

NICE 2014 guidelines recommend offering CBT to all people with schizophrenia. This includes people who have persistent psychotic symptoms, those who are withdrawn and also people in remission. The aim is to promote recovery. It is recommended that CBT consist of at least 16 planned sessions.

CBT, family therapy and art therapy are the main three psychological interventions available for any stage of schizophrenia.

What are the implications?

In this group of people with longstanding schizophrenia and continued symptoms despite the use of clozapine, CBT was an ineffective addition to usual care. This trial does not support the widespread use of CBT in this group of people

People who had received CBT within the previous year were excluded from the trial, and it is unclear how many of the participants had ever been offered or engaged with CBT or other psychological therapy. Therefore it is difficult to know whether there is a subgroup who would benefit more. There may also be a timing issue of starting therapy when a person is ready to do so, rather than in the confines of a trial.

Though the results are disappointing, it highlights the need for alternative options to be developed. It should also not preclude CBT from being offered on an individual basis.

This study was funded by the National Institute for Health Research Health Technology Assessment programme (project number 10/101/02).
Conflicting interests are declared by some of the co-authors. The CBT manual used in this study was developed by the lead researcher.

Background
Although clozapine is the treatment of choice for treatment-refractory schizophrenia, 30–40% of patients have an insufficient response, and others are unable to tolerate it. Evidence for any augmentation strategies is scarce. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for clozapine-resistant schizophrenia.
Methods
We did a pragmatic, parallel group, assessor-blinded, randomised controlled trial in community-based and inpatient mental health services in five sites in the UK. Patients with schizophrenia who were unable to tolerate clozapine, or whose symptoms did not respond to the drug, were randomly assigned 1:1 by use of randomised-permuted blocks of size four or six, stratified by centre, to either CBT plus treatment as usual or treatment as usual alone. Research assistants were masked to allocation to protect against rater bias and allegiance bias. The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months, which provides a continuous measure of symptoms of schizophrenia; PANSS total was also assessed at the end of treatment (9 months). The primary analysis was by randomised treatment based on intention to treat, for all patients for whom data were available. This study was prospectively registered, number ISRCTN99672552. The trial is closed to accrual.
Findings
From Jan 1, 2013, to May 31, 2015, we randomly assigned 487 participants to either CBT and treatment as usual (n=242) or treatment as usual alone (n=245). Analysis included 209 in the CBT group and 216 in the treatment as usual group. No difference occurred in the primary outcome (PANSS total at 21 months, mean difference −0·89, 95% CI −3·32 to 1·55; p=0·48), although the CBT group improved at the end of treatment (PANSS total at 9 months, mean difference −2·40, −4·79 to −0·02; p=0·049). During the trial, 107 (44%) of 242 participants in the CBT arm and 104 (42%) of 245 in the treatment as usual arm had at least one adverse event (odds ratio 1·09, 95% CI 0·81 to 1·46; p=0·58). Only two (1%) of 242 participants in the CBT arm and one (<1%) of 245 in the treatment as usual arm had a trial-related serious adverse event.
Interpretation
At 21-month follow-up, CBT did not have a lasting effect on total symptoms of schizophrenia compared with treatment as usual; however, CBT produced statistically, though not clinically, significant improvements on total symptoms by the end of treatment. There was no indication that the addition of CBT to treatment as usual caused adverse effects. The results of this trial do not support a recommendation to routinely offer CBT to all people who meet criteria for clozapine-resistant schizophrenia; however, a pragmatic individual trial might be indicated for some.
Funding
National Institute for Health Research Technology Assessment programme.

Expert commentary

Clozapine is our ‘go-to’ drug in refractory psychosis, but it’s ineffective or not tolerated in up to half who take it. Talking therapies have an established role in psychosis, but there have been fewer data on their utility in this group.

In this large trial participants were randomised to receive either additional CBT or ‘treatment as normal’.

Disappointingly, CBT did not provide significant benefit. The authors rightly note that their findings do not mean this therapy should not be offered on an individually planned basis – rather, the findings go against a widespread routine roll-out of cognitive behavioural therapy in this group.